title: Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery.
abstract: The direct intraparenchymal administration of oncolytic viral vectors by convection-enhanced delivery (CED) represents a promising new treatment strategy for malignant gliomas. However, there is no evidence to suggest that oncolytic viruses as large as herpes simplex virus-1 (HSV-1) can be administered by CED, as this has not been systematically examined in an animal model. In this study, the administration of a herpes simplex viral vector, HSV1, has been evaluated in detail in the gray and white matter of both rat and pig models, using high flow-rate infusions, co-infusing heparin or preinfusing the tissue with an isotonic albumin solution. Rat HSV-1 infusions at both slow (0.5 μl min(-1)) and high infusion rates (2.5 μl min(-1)) led to extensive tissue damage and negligible cell transduction. Co-infusion with heparin led to extensive hemorrhage. Preinfusion of tissue with an isotonic albumin solution facilitated widespread vector distribution and cell transduction in white matter only. Using this approach in pig brain led to widespread vector distribution with extensive transduction of astrocytes and activated microglia. In rat brain, enhanced green fluorescent protein expression peaked 48 h after vector administration and was associated with a vigorous immune response. These findings indicate that direct infusions of HSV-1-based viral vectors into the brain lead to minimal vector distribution, negligible cell transduction and extensive damage. Tissue preinfusion with an isotonic solution prior to vector administration represents an effective technique for achieving widespread HSV-1 distribution.
authors.affiliation: Department of Neurosurgery, Frenchay Hospital, Bristol, UK.
authors.forename: E
authors.initials: E
authors.lastname: White
authors.forename: A
authors.initials: A
authors.lastname: Bienemann
authors.forename: L
authors.initials: L
authors.lastname: Megraw
authors.forename: C
authors.initials: C
authors.lastname: Bunnun
authors.forename: S
authors.initials: S
authors.lastname: Gill
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000821:virology; D018481:Convection; D016503:Drug Delivery Systems / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000627:therapeutic use; D005910:Glioma / Q000235:genetics / Q000628:therapy*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D051381:Rats; D017208:Rats, Wistar; D018139:Simplexvirus; D013552:Swine
chemical_list: C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins